The vascular disrupting activity of OXi8006 in endothelial cells and its phosphate prodrug OXi8007 in breast tumor xenografts.

Autor: Strecker TE; Department of Chemistry and Biochemistry, Baylor University, Waco, TX 76798-7348, USA., Odutola SO; Institute of Biomedical Studies, Baylor University, Waco, TX 76798-7224, USA., Lopez R; Department of Radiology, The University of Texas Southwestern Medical Center, Dallas, TX 75390-9058, USA., Cooper MS; Department of Chemistry and Biochemistry, Baylor University, Waco, TX 76798-7348, USA., Tidmore JK; Department of Chemistry and Biochemistry, Baylor University, Waco, TX 76798-7348, USA., Charlton-Sevcik AK; Department of Chemistry and Biochemistry, Baylor University, Waco, TX 76798-7348, USA., Li L; Department of Radiology, The University of Texas Southwestern Medical Center, Dallas, TX 75390-9058, USA., MacDonough MT; Department of Chemistry and Biochemistry, Baylor University, Waco, TX 76798-7348, USA., Hadimani MB; Department of Chemistry and Biochemistry, Baylor University, Waco, TX 76798-7348, USA., Ghatak A; Department of Chemistry and Biochemistry, Baylor University, Waco, TX 76798-7348, USA., Liu L; Department of Radiology, The University of Texas Southwestern Medical Center, Dallas, TX 75390-9058, USA., Chaplin DJ; OXiGENE Inc., South San Francisco, CA 94080, USA., Mason RP; Department of Radiology, The University of Texas Southwestern Medical Center, Dallas, TX 75390-9058, USA., Pinney KG; Department of Chemistry and Biochemistry, Baylor University, Waco, TX 76798-7348, USA; Institute of Biomedical Studies, Baylor University, Waco, TX 76798-7224, USA., Trawick ML; Department of Chemistry and Biochemistry, Baylor University, Waco, TX 76798-7348, USA; Institute of Biomedical Studies, Baylor University, Waco, TX 76798-7224, USA. Electronic address: mary_lynn_trawick@baylor.edu.
Jazyk: angličtina
Zdroj: Cancer letters [Cancer Lett] 2015 Dec 01; Vol. 369 (1), pp. 229-41. Date of Electronic Publication: 2015 Sep 01.
DOI: 10.1016/j.canlet.2015.08.021
Abstrakt: This study describes the vascular disrupting ability and the mechanism of action of the indole-based tubulin-binding compound, OXi8006, and its water-soluble phosphate prodrug OXi8007. Treatment of rapidly proliferating human umbilical vein endothelial cells (HUVECs), used as a model for the tumor vasculature, with OXi8006 or OXi8007, caused potent microtubule disruption followed by extensive reorganization of the cytoskeletal network. The mechanism of action involved an increase in focal adhesion formation associated with an increase in phosphorylation of both non-muscle myosin light chain and focal adhesion kinase. These effects were dramatically diminished by an inhibitor of RhoA kinase, a downstream effector of RhoA. Cell cycle blockade at G2/M and cytotoxicity toward rapidly proliferating HUVECs were also observed. Capillary-like networks of HUVECs were disrupted by the action of both OXi8006 and OXi8007. The prodrug OXi8007 exhibited potent and rapid dose-dependent antivascular activity assessed by dynamic bioluminescence imaging (BLI) in an MDA-MB-231-luc breast cancer xenograft mouse model. By 6 hours post treatment, over 93% of the BLI signal was abolished with only a slight recovery at 24 hours. These findings were confirmed by histology. The results from this study demonstrate that OXi8007 is a potent vascular disrupting agent acting through an anti-microtubule mechanism involving RhoA.
(Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)
Databáze: MEDLINE
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